関: mevalonic acid

mevalonic acid

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2014/08/25 03:50:26」(JST)

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Mevalonic acid (MVA) (derived from a contraction of dihydroxymethylvalerolactone) is a key organic compound in biochemistry. The anion of mevalonic acid, the predominant form in biological media, is known as mevalonate. This compound is of major pharmaceutical importance. Drugs, such as the statins, stop the production of mevalonate by inhibiting HMG-CoA reductase.^[1]

Chemistry

Mevalonic acid is very soluble in water and in polar organic solvents. It exists in equilibrium with the lactone, called mevalonolactone, formed by internal condensation of its terminal alcohol and carboxylic acid functional groups.

Biology

Mevalonic acid is a precursor in the biosynthetic pathway, known as the mevalonate pathway, that produces terpenes and steroids. Mevalonic acid is the primary precursor of isopentenyl pyrophosphate (IPP), that is in turn the basis for all terpenoids. Mevalonic acid is chiral and the (3R)-enantiomer is the only one that is biologically active.

Mevalonate pathway

References

^ Endo, A. (1992). "The discovery and development of HMG-CoA reductase inhibitors". Journal of Lipid Research 33 (11): 1569–1582. PMID 1464741.

UpToDate Contents

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English Journal

Molecular regulation of santalol biosynthesis in Santalum album L.

Rani A, Ravikumar P, Reddy MD, Kush A.SourceDepartment of Biotechnology, Vittal Mallya Scientific Research Foundation, Bangalore, 560076, India.
Gene.Gene.2013 Sep 25;527(2):642-8. doi: 10.1016/j.gene.2013.06.080. Epub 2013 Jul 13.
Santalum album L. commonly known as East-Indian sandal or chandan is a hemiparasitic tree of family santalaceae. Santalol is a bioprospecting molecule present in sandalwood and any effort towards metabolic engineering of this important moiety would require knowledge on gene regulation. Santalol is a
PMID 23860319

Analysis of the Dendrobium officinale transcriptome reveals putative alkaloid biosynthetic genes and genetic markers.

Guo X, Li Y, Li C, Luo H, Wang L, Qian J, Luo X, Xiang L, Song J, Sun C, Xu H, Yao H, Chen S.SourceInstitute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China.
Gene.Gene.2013 Sep 15;527(1):131-8. doi: 10.1016/j.gene.2013.05.073. Epub 2013 Jun 10.
Dendrobium officinale Kimura et Migo (Orchidaceae) is a traditional Chinese medicinal plant. The stem contains an alkaloid that is the primary bioactive component. However, the details of alkaloid biosynthesis have not been effectively explored because of the limited number of expressed sequence tag
PMID 23756193

2-Methyl-l-erythritol glycosides from Gardenia jasminoides.

Yang L, Peng K, Zhao S, Zhao F, Chen L, Qiu F.SourceDepartment of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China; Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Fitoterapia.Fitoterapia.2013 Sep;89:126-30. doi: 10.1016/j.fitote.2013.05.018. Epub 2013 May 31.
Two new glycosides, 2-methyl-l-erythritol-4-O-(6-O-trans-sinapoyl)-β-d-glucopyranoside (1) and 2-methyl-l-erythritol-1-O-(6-O-trans-sinapoyl)-β-d-glucopyranoside (2), along with two known triterpenoids (3-4), four quinic acid derivatives (5-8) and one flavonoid (9) were isolated from the fruit of
PMID 23727470

Japanese Journal

Thermodynamic Evaluation of the Binding of Bisphosphonates to Human Farnesyl Pyrophosphate Synthase

Kawasaki Yuko,Sekiguchi Mitsuhiro,Kawasaki Masashi,Hirakura Yutaka
Chemical and Pharmaceutical Bulletin, 2014
… BPs with nitrogen-containing side chains (N-BPs) are known to act as inhibitors for farnesyl pyrophosphate synthase (FPPS), a key enzyme in the mevalonate pathway. …
NAID 130003381818

Probable Novel MEP Pathway Inhibitor and Its Binding Protein, IspG

NAKAGAWA Kazuya,TAKADA Kentaro,IMAMURA Nobutaka
Bioscience, Biotechnology, and Biochemistry 77(7), 1449-1454, 2013-07
NAID 40019721553

Biochemical evidence supporting the presence of the classical mevalonate pathway in the thermoacidophilic archaeon Sulfolobus solfataricus

Nishimura Hiroto,Azami Yasuhiro,Miyagawa Masahito [他]
The journal of biochemistry 153(5), 415-420, 2013-05
NAID 40019646755

Related Pictures

★リンクテーブル★

リンク元	「HMG-CoA還元酵素阻害薬」「メバロン酸」「mevalonic acid」
拡張検索	「mevalonate kinase deficiency」

「HMG-CoA還元酵素阻害薬」

Mevalonic acid
	IUPAC name (3R)-3,5-Dihydroxy-3-methylpentanoic acid
Identifiers
CAS number	150-97-0
PubChem	439230
ChemSpider	388367
KEGG	C00418
ChEBI	CHEBI:17710
Jmol-3D images	Image 1
	SMILES C[C@@](O)(CCO)CC(=O)O ;
	InChI InChI=1S/C6H12O4/c1-6(10,2-3-7)4-5(8)9/h7,10H,2-4H2,1H3,(H,8,9)/t6-/m1/s1; Key: KJTLQQUUPVSXIM-ZCFIWIBFSA-N InChI=1/C6H12O4/c1-6(10,2-3-7)4-5(8)9/h7,10H,2-4H2,1H3,(H,8,9)/t6-/m1/s1; Key: KJTLQQUUPVSXIM-ZCFIWIBFBE ;
Properties
Molecular formula	C6H12O4
Molar mass	148.16 g mol−1
	Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
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	Infobox references

　　[★]

英: HMG-CoA reductase inhibitor
同: ヒドロキシメチルグルタリルコエンザイムA還元酵素阻害薬 hydroxymethylglutaryl-CoA reductase inhibitor。スタチン statin
関: 高脂血症治療薬、高脂血症、コレステロールの生合成。HMG-CoA還元酵素 HMG-CoA reductase

特徴

強力なコレステロール低下作用

アトルバスタチンの場合

血清TC低下率30%

血清LDL-C低下率41%

血清TG低下作用

TG250-350mg/dl　380

TG350-450mg/dl　470

安全性が高い(プラバスタチンのみ)

プラバスタチンは水溶性。(⇔脂溶性だとどこでも入っていく→全身性に作用する)

プラバスタチンの輸送担体は肝臓にしかない→臓器選択性↑→安全性↑

CYP3A4との相互作用がない

種類

CYP 代謝による分類	薬物	商品名	性質1)		CYP代謝 2)	代謝物の活性 3)	排泄形態 3)	bioavailability (%) 3)	尿中排泄 (%) 2)	半減期 (hr) 2)
CYP 代謝による分類	薬物	商品名	定性	定量(LogP)	CYP代謝 2)	代謝物の活性 3)	排泄形態 3)	bioavailability (%) 3)	尿中排泄 (%) 2)	半減期 (hr) 2)
非代謝型	プラバスタチン	メバロチン	水溶性	-0.47	ほとんどなし	ー	未変化体	18	20	1ー2
	ロスバスタチン	クレストール	水溶性			ー 5)	未変化体 5)	29	10 5)	15～19 5)
	ピタバスタチン	リバロ	脂溶性	1.49		ー	未変化体	60	＜2	11
代謝型	フルバスタチン	ローコール	脂溶性	1.73	CYP2C9	なし	代謝物	10-35	＜6	1.2
	シンバスタチン	リポバス	脂溶性	4.4	CYP3A4	あり	代謝物	＜5	13	1ー2
	アトルバスタチン	リピトール	脂溶性	1.53	CYP3A4	あり	(データ無し)	12	2	14
1)Prog Med, 18:957-962,1998. 2)Heart, 85:259-264,2001. 3)PHarmacol Ther, 80:1-34 改変 4)興和(株)社内資料 5)添付文書

作用機序

HMG-CoA reductaseを競合阻害→肝内コレステロール産生↓→肝LDL受容体発現↑→血中LDL↓

HMG-CoA reductaseはHMG-CoAからmevalonate産生を触媒

副作用

1. 横紋筋融解症

原因：メバロン酸合成↓→CoQ↓→ミトコンドリア機能異常。Cl^-の細胞膜透過性の変化

2. CYPを介する薬物相互作用

CYP	代謝されるスタチン	代謝される薬物	強く阻害する薬物
CYP2C9	フルバスタチン	ワーファリンジクロフェナクフェニトイン	サルファ剤 ST合剤
CYP3A4	シンバスタチンセリバスタチンアトルバスタチン	ニフェジピンシクロスポリンジルチアゼムなど多数	エリスロマイシンシメチジンイトラコナゾールベラパミル

薬物相互作用によりCYP3A4の働きが阻害されると、横紋筋融解症の引き金となりうる

3. 肝障害

脂溶性HMG-CoA還元酵素阻害薬は重篤な肝障害を起こす

4. CK上昇

This was suggested by a study showing greater increases in post-marathon CK levels in individuals receiving statins; older runners receiving statins exhibited more susceptibility to CK elevations than younger runners. These elevations in CK were, however, mild and subclinical, which suggests that trained individuals need not discontinue statin therapy prior to a race.(uptodate)

軽度であれば(マラソンの)習熟者はレース前にスタチンを中止をする必要がないことを示唆する。